Loss of BAP1 Expression in Atypical Mesothelial Proliferations Helps to Predict Malignant Mesothelioma

Our plain-English summary of Loss of BAP1 Expression in Atypical Mesothelial Proliferations Helps to Predict Malignant Mesothelioma, by R. Pillappa, J.J. Maleszewski, W.R. Sukov, et al (The American Journal of Surgical Pathology, 2018).

The study

• Authors: R. Pillappa, J.J. Maleszewski, W.R. Sukov, P.P. Bedroske, P.T. Greipp, J.M. Boland, E.S. Yi, T. Peikert, M.C. Aubry, A.C. Roden
• Journal: The American Journal of Surgical Pathology
• Published: 2018;42(2):256-263
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Distinguishing reactive mesothelial proliferation from malignant mesothelioma (MM) can be difficult, particularly on small biopsies. In this scenario, a diagnosis of atypical mesothelial proliferation might be rendered. However, the distinction between a reactive process and MM is important for prognosis and treatment. Recently, loss of BRCA1-associated protein 1 (BAP1) expression and/or homozygous deletion of CDKN2A were identified in some MM, but not in reactive mesothelial proliferations. We studied 34 cases of atypical mesothelial proliferation from our institutional files (1993 to 2016) for BAP1 expression, deletion of CDKN2A, and clinical outcome. Fifteen of 34 patients (44%) were subsequently diagnosed with MM. BAP1 expression was lost in 6 of these 15 (40%) patients. Ten of 15 (67%) patients died of disease within a median time of 18.2 months. BAP1 expression was also lost in 1 case of probable MM. In this case atypical mesothelial proliferation was identified in the pleura during a lobectomy procedure for lung adenocarcinoma. Follow-up of 57.0 months was remarkable for visceral and parietal pleural thickening with continued unilateral effusion identified on imaging studies but no subsequent definitive diagnosis of MM. CDKN2A studies by fluorescence in situ hybridization (performed in 31 cases) found no homozygous deletion of that gene in any case. In conclusion, loss of BAP1 expression in atypical mesothelial proliferation helps to predict MM and is a useful adjunct test in these cases. Homozygous deletion of CDKN2A in mesothelial cell proliferations did not prove to be useful to predict MM in cases of atypical mesothelial proliferation.

In plain English

This study from Mayo Clinic in Rochester, Minnesota, looked back at 34 biopsies, from 1993 to 2016, that had been diagnosed as "atypical mesothelial proliferation". These were abnormal-looking lining cells of the pleura, pericardium or peritoneum that could not be firmly called malignant mesothelioma. The authors tested the tissue for loss of a protein called BAP1 and for loss of both copies of a gene called CDKN2A, then compared the results with what later happened to each patient. During a median follow-up of 31.7 months, 15 of the 34 patients (44.1%) were diagnosed with malignant mesothelioma. BAP1 was lost in 6 of those 15, in one patient judged to have probable mesothelioma, and in none of the 18 patients without mesothelioma. No case among the 31 tested for CDKN2A showed loss of both copies. The authors concluded that BAP1 loss can help support a mesothelioma diagnosis, but that retained BAP1 cannot rule mesothelioma out. They found the CDKN2A test was not useful in these cases. The article does not report asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective diagnostic study of archived pathology cases (case series with follow-up), testing BAP1 immunostaining and CDKN2A FISH
• Who was studied: 34 patients with a biopsy diagnosis of atypical mesothelial proliferation at Mayo Clinic Rochester, 1993 to 2016. Of 37 identified, 3 were excluded for insufficient tissue. 22 were men (64.7%), and the median age was 68.3 years. Sites were pleura in 21, pericardium in 3 and peritoneum in 10. The proliferations were mostly epithelioid, with 2 biphasic.
• Exposure: No asbestos or other exposure was studied or reported. The study examined two laboratory markers in biopsy tissue: BAP1 protein expression by immunostaining, and CDKN2A gene deletion by fluorescence in situ hybridization (FISH).
• Main results:
  • During a median follow-up of 31.7 months, 15 of 34 patients (44.1%) were diagnosed with malignant mesothelioma, 1 was considered probable mesothelioma, and 18 were considered not to have mesothelioma.
  • BAP1 expression was lost in 7 of 34 cases (20.6%) overall.
  • BAP1 expression was lost in 6 of 15 patients (40%) later diagnosed with mesothelioma, in the 1 probable mesothelioma case, and in 0 of the 18 patients without mesothelioma.
  • With the probable mesothelioma case counted as mesothelioma, BAP1 loss had a sensitivity of 43.7%, a specificity of 100.0%, a positive predictive value of 100.0% and a negative predictive value of 66.7% for mesothelioma.
  • None of the 31 cases tested showed homozygous deletion (loss of both copies) of CDKN2A. Three showed heterozygous deletion and 3 showed additional copies.
  • Among the 15 patients later diagnosed with mesothelioma, 10 (66.6% per Table 3) died, all of the disease. The median time from biopsy to death was 18.2 months (range 1.1 to 91.2).
• The authors' conclusion: The authors concluded that BAP1 loss can be useful in making a diagnosis of mesothelioma even without invasion or tumor-forming growth. They also concluded that retained BAP1 cannot be used to predict the absence of mesothelioma, and that homozygous CDKN2A deletion did not prove useful for predicting mesothelioma in atypical mesothelial proliferations.
• Limitations the authors state:
  • The biopsies were generally small, and sampling bias may have played a role in the CDKN2A findings.
  • Many cases had only sparse tissue, with few mesothelial cells.
  • Some cases may have been precursor lesions, and tumor heterogeneity is possible. Either could explain the lower rate of BAP1 loss than reported elsewhere.
  • Lead-time bias from biopsying early-stage disease might have artificially increased survival times.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Atypical Mesothelial Proliferation, Malignant Mesothelioma, Prognosis, Homozygous Deletion, CDKN2A, Pleura, Lung Adenocarcinoma.

Related studies

• BAP1 (BRCA1-associated protein 1) is a highly specific marker for differentiating mesothelioma from reactive mesothelial proliferations — M. Cigognetti, S. Lonardi, et al. (2015)
• BAP1 loss is unusual in well-differentiated papillary mesothelioma and may predict development of malignant mesothelioma — H.E. Lee, J.R. Molina, et al. (2018)
• Utility of BAP1 Immunohistochemistry and p16 (CDKN2A) FISH in the Diagnosis of Malignant Mesothelioma in Effusion Cytology Specimens — H.C. Hwang, B.S. Sheffield, et al. (2016)
• Sarcomatoid Mesothelioma: A CDKN2A molecular analysis of 53 cases with immunohistochemical correlation with BAP1 — M. Zaleski, N. Kalhor, et al. (2020)
• Loss of expression of BAP1 predicts longer survival in mesothelioma — M. Farzin, C.W. Toon, et al. (2015)
• New Markers for Separating Benign From Malignant Mesothelial Proliferations: Are We There Yet? — A. Churg, B.S. Sheffield, et al. (2016)

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